Long-acting low-addiction hnk derivative and preparation method therefor

ABSTRACT

The present application relates to a compound having the effects of being an antidepressant, anesthetizing, alleviating pain, improving cognitive functions, protecting lungs, preventing or treating amyotrophic lateral sclerosis or preventing or treating complex regional pain syndrome. Compared with existing known HNK compounds, the compound provided in the present application has a longer drug efficacy period. Moreover the compound provided in the present application basically does not produce addiction.

CROSS-REFERENCE TO RELATED APPLICATION

The application is the U.S.A. national phase entry of InternationalApplication No. PCT/CN2020/112360, filed on Aug. 31, 2020 and entitled“LONG-ACTING LOW-ADDICTION COMPOUND AND PREPARATION METHOD THEREFOR”,the disclosure of which is hereby incorporated by reference in itsentirety.

TECHNICAL FIELD

The disclosure relates to the field of pharmaceuticals, in particular toa long-acting low-addiction compound for treating depression, includingcomplex regional pain syndrome (CRPS) and a preparation method therefor.

BACKGROUND

Ketamine is a representative of phencyclidine-based intravenousanesthetics commonly used clinically, and is one of anesthetics thathave developed rapidly clinically and in basic research in recent years.In clinical practice, it is often used to meet the anesthesia needs ofpediatrics, obstetrics, perioperative period and patients with specialdiseases, because of its rapid induction, short action time, quickrecovery, and less impact on the respiratory and circulatory systems.

Ketamine was first synthesized in 1962, used in human body in 1965, andofficially approved by FDA for clinical use in 1970. The typical“dissociative anesthesia” and short-acting precise analgesia made itvery popular, but it was found subsequently having psychiatric sideeffects. With the rapid development of other intravenous anesthetics,clinical use of ketamine had been greatly reduced. In the past 10 years,with the research on the usage and dosage of ketamine and the discoveryof its effects of antiinflammatory, antidepressant, neuroprotective,analgesic and so on, the medical community’s interest in ketamine hasrevived.

Ketamine has the functions of strong analgesia, forgetting, retainingspontaneous breathing and airway protective reflex, and maintaininghemodynamic stability, which makes ketamine play an important role inpre-hospital anesthesia and analgesia all along. Ketamine has bothneurotoxic and neuroprotective effects.

Ketamine has an effect on postoperative cognitive function. Someresearchers tested 50 children who received ketamine anesthesia andfound that ketamine general anesthesia could reduce the cognitivefunction of the children 6 hours after operations, but had no effect onthe cognitive function 24 hours after the operations. Hudetz et al.found that administration of 0.5 mg/kg ketamine during induction ofgeneral anesthesia could reduce the incidence of postoperative cognitiveimpairment one week after cardiac surgery. In recent years, numerousclinical trials have confirmed that administration of a single smalldose of ketamine during surgery can reduce the incidence ofpostoperative cognitive impairment.

Ketamine has analgesic effect. Sub-anesthetic doses of ketamine areoften used for anti-hyperalgesia and the treatment of acute and chronicpain. It has been proved by research that gargling with ketamine-salinemixture before anesthesia induction can significantly reduce theincidence and severity of postoperative sore throat caused by trachealintubation under general anesthesia. Use of opioids during surgeryincreases the dose of opioids used for postoperative analgesia, which iscalled opioid tolerance. It is clinically found that the use of ketaminecan prevent opioid tolerance, reverse morphine tolerance, and enhancethe analgesic effect of morphine. Some studies have confirmed thatintraoperative use of small dose ketamine can prevent postoperativehyperalgesia induced by remifentanil. Cagla et al. found that in thecase that 0.15 mg/kg of ketamine was administered intravenously topatients after undergoing knee arthroscopy, postoperative analgesiasatisfaction was significantly improved, and the sedation score waslower than that of the group administrated with ketamine combined withmidazolam.

Ketamine has a lung protective effect. In recent years, ketamine hasbeen found to have a significant lung protective effect. Clinical trialshave confirmed that administration by intravenous or nebulization beforeone-lung ventilation in thoracic surgery can reduce levels ofinflammatory factors in blood, in which nebulization inhalation is morebeneficial to cardiovascular system and airway pressure, and the effectof nebulization at the pulmonary ventilation lung is better than at twolungs. Ketamine is also commonly used clinically in a rescue of fatalasthma attacks when conventional treatment fails, and its use isrecognized to improve prognosis.

Ketamine has an antidepressant effect. In 2000, Berman et al. reportedfor the first time that scores of Hamilton Depression Scale decreased by50% or more in more than 50% patients within 72 hours after a singleintravenous injection of sub-anesthetic dose of ketamine (0.5 mg/kg). Inrecent years, more animal and clinical studies have further confirmedthe antidepressant effect of ketamine. Ketamine is also used asanesthesia for electroconvulsive therapy in depressed patients.

The patent application No.: CN 201280062294X, entitled “Use of(2R,6R)-hydroxynorketamine, (S)-dehydronorketamine and OtherStereoisomers of Dehydrogenation and Hydroxylation Metabolites of(R,S)-ketamine in treatment of depression and neuropathic pain”,discloses that CNS (central nervous system) side effects are related tothe activity of (R,S)-ketamine to NMDA receptors. Based on ketamine,(2R, 6R; 2S, 6S)-hydroxynorketamine (HNK) was studied and synthesized.The compound has no activity to NMDA receptor, thus avoiding possibleside effects, and is said to have therapeutic efficacies for bipolardepression, major depressive disorder, Alzheimer’s dementia, amyotrophiclateral sclerosis, complex regional pain syndrome (CRPS), chronic pain,or neuropathic pain.

In our experimental studies, it was found that(2R,6R;2S,6S)-hydroxynorketamine (HNK) did not have a long efficacyafter administration, and basically lost activity within one week, whichseriously limits a desired long-term effect in the treatment ofdepression. At the same time, our studies also found that use of HNKwould produce a certain degree of addiction, which caused adverseeffects on patients’ body and mind. Therefore, how to modify thestructure of (2R,6R;2S,6S)-hydroxynorketamine (HNK) to obtain a drugwith longer efficacy and lower addiction is the problem to be solved toobtain a great therapeutic potential.

SUMMARY

The disclosure relates to a compound having an efficacy inanti-depression, mitigating anxiety and post-traumatic stress syndrome,anesthesia, alleviating pain, improving cognitive function, lungprotection, preventing or treating amyotrophic lateral sclerosis orpreventing or treating complex regional pain syndrome.

Compared with the existing known HNK compounds, the compound of thedisclosure has a longer efficacy duration, which is specificallymanifested in that the known HNKs are metabolized within one week andhave no activity, while the efficacy of the compound of the disclosurecan last for more than one week, specifically for more than 7 days, morethan 10 days, more than 14 days and the like. Moreover, the compound ofthe disclosure is substantially non-addictive and are 2 times, 5 times,10 times, or 20 times less addictive than the known HNK compounds.

The disclosure provides a compound represented by Formula I:

in which m is an integer from 0 to 3, and n is an integer from 0 to 4;R₁ and R₂ are each independently one or more selected from a groupconsisting of H, halogen, hydroxyl, amino, cyano, substituted orunsubstituted C₁-C₆ alkyl group, substituted or unsubstituted C₂-C₆alkenyl group, substituted or unsubstituted C₂-C₆ alkynyl group,substituted or unsubstituted C₃-C₁₀ cycloalkyl group, substituted orunsubstituted C₂-C₁₀ heterocyclic group, substituted or unsubstitutedC₁-C₆ alkoxy group, substituted or unsubstituted mono- and di- C₁-C₆alkylamino group, substituted or unsubstituted aryl group, andsubstituted or unsubstituted heteroaryl group; R₃ is halogen; R₄ isselected from a group consisting of H, substituted or unsubstitutedC₁-C₆ alkyl group, substituted or unsubstituted C₁-C₈ acyl group,substituted or unsubstituted aryl acyl group, and substituted orunsubstituted heteroarylacyl group; R₅ is selected from a groupconsisting of substituted or unsubstituted C₃-C₁₀ cycloalkyl group,substituted or unsubstituted C₂-C₁₀heterocyclic group, substituted orunsubstituted aryl group, and substituted or unsubstituted heteroarylgroup; R₆ and R₇ are independently selected from a group consisting ofH, substituted or unsubstituted C₁-C₆ alkyl group, substituted orunsubstituted C₂-C₆ alkenyl group, substituted or unsubstituted C₂-C₆alkynyl group, substituted or unsubstituted C₃-C₁₀ cycloalkyl group,substituted or unsubstituted C₂-C₁₀heterocyclic group, substituted orunsubstituted aryl group, substituted or unsubstituted heteroaryl group,substituted or unsubstituted C₁-C₈ acyl group, substituted orunsubstituted aryl acyl group, and substituted or unsubstitutedheteroaryl acyl group, or a salt, stereoisomer or tautomer of thecompound, or R₆ and R₇, together with N atom to which R₆ and R₇ areconnected, form a substituted or unsubstituted 3 to 10-memberedmonocyclic or bicyclic structure.

A group is substituted mentioned above means that the group issubstituted by a substituent selected from OH; NH₂; C₁-C₁₀ alkyl,alkenyl or alkynyl group; C₁-C₁₀ alkylamine group; sulfhydryl group;C₁-C₁₀ alkyl-sulfhydryl group; C₁-C₂₀ alkoxy group; C₁-C₁₀ carbonylgroup; C₃-C₁₀cycloalkyl group; 3 to 10-membered heterocyclic group withone or more heteroatoms selected from N, S, O and P; C₆-C₂₀ aryl; C₂-C₂₀heteroaryl group; nitrocyano; and halogen.

Preferably, the above-mentioned compound is represented by Formula II:

Preferably, the above-mentioned compound is represented by Formula III:

Preferably, the above-mentioned compound is represented by Formula IV:

Preferably, the above-mentioned compound is the following compound:

Preferably, the above-mentioned compound is the following compound:

The disclosure also provides a compound as follows:

in which R₈ is H or a protecting group, or a salt, stereoisomer ortautomer thereof.

Preferably, the above-mentioned compound has the following structure:

or a salt, stereoisomer or tautomer thereof.

Preferably, the above-mentioned compound has the following structure:

or a salt, stereoisomer or tautomer thereof.

The disclosure also provides a pharmaceutical composition including thecompound, or a salt, stereoisomer or tautomer thereof mentioned above,and optionally a pharmaceutically acceptable carrier.

The disclosure also provides a preparation method of a compoundincluding preparation steps below:

Use of any of the above compounds in preparation of a medicament foranesthesia, alleviating pain, improving cognitive function, lungprotection, anti-depression, mitigating anxiety, post-traumatic stresssyndrome, amyotrophic lateral sclerosis and complex regional painsyndrome.

The pain includes: chronic pain or neuropathic pain. The depressionincludes: bipolar depression, major depressive disorder. The anxiety andpost-traumatic stress syndrome are mitigated. ; Mitigating cognitivefunction includes prevention or treatment of Alzheimer’s dementia,Parkinson’s disease and so on.

With respect to all of the above diseases, the use also coverspreventive or therapeutic effects.

Stereoisomers of all the above compounds include enantiomers anddiastereomers.

The disclosure is not limited to any particular tautomer, but includesall tautomer forms in the case that all of the above compounds arepresent in different tautomer forms.

All compounds described above include compounds having all possibleisotopes of the atoms present in the compounds. Isotopes include thoseatoms with the same atomic number but different mass numbers. Generally,for example, without limitation, isotopes of hydrogen include tritiumand deuterium, and isotopes of carbon include ¹¹C, ¹³C and ¹⁴C.

The disclosure also provides a pharmaceutical composition, and thecompound disclosed herein may be administered as a pure chemical, but ispreferably administered as a pharmaceutical composition. Accordingly,the disclosure provides a pharmaceutical composition comprising acompound or a pharmaceutically acceptable salt and at least onepharmaceutically acceptable carrier. The pharmaceutical composition maycontain the compound or a salt thereof as the only active agent, butpreferably contains at least another active agent. In some embodiments,the pharmaceutical composition is an oral dosage form which containsabout 0.1 mg to about 1000 mg, about 1 mg to about 500 mg, about 10 mgto about 200 mg of a compound of Formula I and optionally about 0.1 mgto about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about800 mg, or about 200 mg to about 600 mg of other active agent(s) in aunit dosage form.

The compounds disclosed herein may be administered orally, topically,parenterally, by inhalation or spray, sublingually, transdermally, byoral administration, rectally, as an ophthalmic solution, or by othermeans in a dose unit formulation comprising a conventionalpharmaceutical carrier. The pharmaceutical composition can be formulatedinto any medicinal forms, such as aerosol, cream, gel, pill, capsule,tablet, syrup, transdermal patch, or ophthalmic solution. Some dosageforms, such as tablet and capsule, may be subdivided into appropriatedosage unit forms containing appropriate amount of an active component,such as an effective amount for achieving the desired purpose.

The carriers include excipients and diluents, and must be ofsufficiently high purity and sufficiently low toxicity to be suitablefor administration to a patient to be treated. The carrier may be inertor it may itself have medicinal benefits.

The carrier includes, but is not limited to, a binder, a buffer, acolorant, a diluent, a disintegrant, an emulsifier, a flavoring agent, aglidant, a lubricant, a preservative, a stabilizer, a surfactant, atableting agent or a wetting agent. Some carriers may belong to morethan one categories, e.g. a vegetable oil may be used as a lubricant insome formulations or as a diluent in others. Exemplary pharmaceuticalcarriers include sugar, starch, cellulose, powdered tragacanth, malt,gelatin, talc and vegetable oils. An optional active agent may beincluded in the pharmaceutical composition, and does not substantiallyaffect the activity of the compound of the disclosure.

The compound or a salt thereof of the disclosure may be the only activeagent to be administered or may be administered in combination withother active agents. For example, the compound of the disclosure may beadministered in combination with another active agent selected from anyof the following.

Antidepressant: escitalopram oxalate, fluoxetine, paroxetine,duloxetine, sertraline, citalopram, bupropion, venlafaxine, duloxetine,naltrexone, mirtazapine, venlafaxine, atomoxetine, bupropion, doxepin,amitriptyline, clomipramine, nortriptyline, buspirone, aripiprazole,clozapine, loxapine, olanzapine, quetiapine, risperidone, ziprasidone,carbamazepine, gabapentin, lamotrigine, phenytoin, pregabalin,donepezil, galanthamine, memantine, rivastigmine, tramiprosate, or theirpharmaceutically active salts or prodrugs, or combinations thereof.

Medicines for schizophrenia: aripiprazole, lurasidone, asenapine,clozapine, ziprasidone, risperidone, quetiapine, trifluoperazine,olanzapine, loxapine, flupentioxol, perphenazine, haloperidol,chlorpromazine, flupenazine, fluphenazine and paliperidone.

Medicines for Alzheimer’s dementia: donepezil, rivastigmine,galantamine, memantine.

Medicine for ALS: riluzole.

Medicines for pain: acetaminophen; aspirin; NSAIDS which includediclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen,indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid,meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam,sulindac, Tolmetinopiods; Cox-2 inhibitors such as celecoxib; andanesthetic analgesics such as buprenorphine, butorphanol, codeine,dihydrocodeinone, hydromorphone, levorphanol, pethidine, methadone,morphine, nalbuphine, oxycodone, oxymorphinone, pentazocine,propoxyphene; and central analgesics such as tramadol.

The foregoing list of other active agents is exemplary and notcompletely included. Other active agents not included in the above listmay also be administered in combination with the compound of Formula I.Although in some embodiments, other active agents may be administeredwith a dose less than the generally prescribed and, in some cases, lessthan the approved minimum dose, other active agents may be administeredin accordance with its approved prescribed information.

The disclosure includes a method for treating depressive disorders,particularly, bipolar depression and major depressive disorder, andparticularly for treating treatment-resistant depression, in which theeffective amount of the compound is a dose effectively to reducedepressive symptoms. The reduction of depressive symptoms meansachieving a reduction of 50% or more of the symptoms identified on adepressive symptom rating scale, or a score on HRSD₁₇ of less than orequal to 7, or a score on QID-SR₁₆ of less than or equal to 5, or ascore on MADRS of less than or equal to 10.

The disclosure provides an effective amount to reduce pain (oranalgesia), in which the reduction of pain means achieving a reductionof 50% or greater of pain according to the pain rating scale.

Terminology Definitions

“Stereoisomers” are compounds that have the same chemical compositionbut differ in the arrangements of atoms or groups in space.

“Diastereomers” are stereoisomers that have two or more chiral centersand are not mirror images of each other. Diastereomers have differentphysical properties, such as melting points, boiling points, spectralproperties and reactivities. A mixture of diastereomers can be separatedunder high resolution analysis processes such as electrophoresis,crystallization, in the presence of resolving agents or withchromatography, for example, chiral HPLC columns.

“Enantiomers” refers to two stereoisomers of a compound that arenon-superimposable mirror images of each other. A mixture of enantiomerswith a ratio of 50:50 is referred to as a racemic mixture or a racemate,which may generate during a chemical reaction or a processing wherestereoselectivity or stereospecificity is no longer present.

“Alkyl” includes a saturated aliphatic hydrocarbon group with a branchedor straight chain and has a specified number of carbon atoms, typicallyfrom 1 to about 12 carbon atoms. The term C₁-C₆ alkyl group used in thetext represents an alkyl group having 1 to about 6 carbon atoms. WhenC₀-C_(n) alkyl used with another group in the text, taking (phenyl)C₀-C₄ alkyl as an example, the specified group, in this case, is phenylgroup either directly bonded by a single covalent bond (C₀) or bonded byconnected with an alkyl chain having a specified number of carbon atoms(in this case, 1 to about 4 carbon atoms). Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, 3-methylbutyl, tert-butyl, n-pentyl and secondary pentyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain thatincludes one or more unsaturated carbon-carbon bonds which may exist atany stable point along the chain. The alkenyl group described hereingenerally has 2 to about 12 carbon atoms. Preferably, the alkenyl groupis a lower alkenyl group, which has 2 to about 8 carbon atoms, such as:C₂-C₈, C₂-C₆ or C₂-C₄ alkenyl group. Examples of an alkenyl groupinclude vinyl, propenyl and butenyl.

“Alkoxy” refers to an alkyl group as defined above having a specifiednumber of carbon atoms bonded by an oxygen bridge. Examples of an alkoxygroup include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and3-methylpentyloxy.

Halogens are well known in the art, preferably F, Cl, Br, I.

The term “heterocyclic ring” represents a 5- to 8-membered saturatedring, partially unsaturated ring, or aromatic ring containing 1 to about4 heteroatoms selected from N, O and S with the remaining ring atomsbeing carbon; or a 7- to 11-membered saturated ring, partiallyunsaturated ring, or aromatic heterocyclic system; and a 10- to15-membered tricyclic ring system containing at least one heteroatomselected from N, O, or S in the polycyclic ring system and up to about 4heteroatoms independently selected from N, O and S are contained in eachring of the polycyclic ring system. Unless otherwise specified, theheterocyclic ring may be bonded to a group substituted at any heteroatomor any carbon atom and obtaining a stable structure. When indicated, theheterocyclic ring described herein may be substituted at a carbon or anitrogen atom as long as the resulting compound is stable. Nitrogenatoms in the heterocyclic ring may optionally be quaternized. Preferablya total number of heteroatoms in the heterocyclic group is not greaterthan 4 and preferably a total number of S and O atoms in theheterocyclic group is not greater than 2, more preferably not greaterthan 1. Examples of a heterocyclic group include: pyridyl, indolyl,pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazol, furyl,phenylthio, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolyl,pyrrolyl, pyrazolyl, benzo[b]thiophenyl, isoquinolinyl, quinazolinyl,quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl,5,6,7,8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furyl, thienyl,pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyland pyrrolidinyl.

“Aryl or heteroaryl” represents a stable 5- or 6-membered monocyclic orpolycyclic ring containing 1 to 4, or preferably 1 to 3 heteroatomsselected from N, O and S and the remaining ring atoms being carbon. Whenthe total number of S and O atoms in the heteroaryl group exceeds 1,these heteroatoms are not adjacent to each other. Preferably, the totalnumber of S and O atoms in a heteroaryl group is not greater than 2. Itis especially preferred that the total number of S and O atoms in aheteroaryl group is not greater than one. Nitrogen atom in theheterocyclic ring may optionally be quaternized. When specified, theseheteroaryl groups may also be substituted with carbon or non-carbonatom(s) or group(s). Such substitution may include fusing with a 5- to7-membered saturated ring group optionally containing 1 or 2 heteroatomsindependently selected from N, O, and S, so as to form, for example,[1,3] dioxazolo [4,5-c]pyridyl. Examples of a heteroaryl group include,but are not limited to: pyridyl, indolyl, pyrimidinyl, pyridizinyl,pyrazinyl, imidazolyl, oxazolyl, furyl, phenylthio, thiazolyl,triazolyl, tetrazolyl, isoxazolyl, quinolyl, pyrrolyl, pyrazolyl,benzo[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl,isoindolyl or 5,6,7,8-tetrahydroisoquinoline. An aryl group ispreferably phenyl, naphthyl, etc.

“Depressive disorder” includes low mood, decreased interest inactivities, decreased mental activity or irritability, altered appetite,inattention or indecision, excessive guilt or low self-esteem; andsuicide idea which may occur in the case of mood disorders due todepression, bipolar depression, other diseases or conditions,substance-induced mood disorders, or mood disorders due to other unknownetiologies . It can also co-exist with a variety of other mentaldisorders, including but not limited to mental disorders, cognitivedisorders, eating disorders, anxiety disorders and personalitydisorders. The longitudinal course, history, type of symptoms, andetiology help to distinguish the various forms of mood disorders fromone another.

“A salt of a compound” refers to a derivative of the disclosed compoundin which the parent compound is modified by addition of a non-toxic acidor base to prepare the salt thereof, and also refers to apharmaceutically accepted solvate, including hydrate, of the compoundand the salt thereof. Examples of a pharmaceutically accepted saltinclude, but are not limited to, an inorganic or organic acid additionsalt of a basic residue such as amine, a base or organic addition saltof an acidic residue such as carboxylic acid, and the like, or acombination of one or more of the above salts. The pharmaceuticallyaccepted salts include nontoxic salts and quaternary ammonium salts ofthe parent compound formed from such as nontoxic inorganic or organicacids. For example, non-toxic acidic salts include those derived frominorganic acids, such as hydrochloric, hydrobromic acid, sulfuric acid,sulfamic acid, phosphoric acid, nitric acid, etc. Other acceptableinorganic salts include metal salts such as sodium salt, potassium saltand cesium salt, etc., and alkaline earth metal salts such as calciumsalt, magnesium salt, etc., and combinations of one or more of the abovesalts.

An organic salt of the compound includes a salt prepared from an organicacid such as acetic acid, trifluoroacetic acid, propionic acid, succinicacid, glycolic acid, stearic acid, lactic acid, malic acid, tartaricacid, citric acid, ascorbic acid, pamoic acid, maleic acid,hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid,salicylic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-aminobenzenesulfonic acid, 2-acetylbenzene acid,fumaric acid, p-toluenesulfonic acid, methanesulfonic acid,ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH₂)_(n)-COOH(in which n is 0 to 4); an organic amine salt, such as triethylaminesalt, pyridine salt, methylpyridine salt, ethanolamine salt,triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.; and an amino acid salt, such as arginine,aspartate, glutamate, etc., and combinations of one or more of the abovesalts.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 . shows the antidepressant effects of a drug with different doseswithin 7 days;

FIG. 2 . shows the antidepressant effects of Compounds C and D;

FIG. 3 . shows the non-sensitization effect of Compound I5;

FIG. 4 . shows the behavioral sensitization effect of Compound C;

FIG. 5 . shows the behavioral sensitization effect of Compound D;

FIG. 6 . shows the non-position preference effect of Compound I5 onmice;

FIG. 7 . shows the induced position preference of Compound 7; and

FIG. 8 . shows the induced position preference of Compound D.

DETAILED DESCRIPTION Example 1: Synthesis of(2R,6R)-6-Hydroxynorketamine (HNK)

Step 1: To a two-neck flask or a three-neck flask, added were 50 g ofmagnesium powder, and dropwise a mixed solution of tetrahydrofuran (THF)and 119.2 g of bromocyclopentane slowly after initiation. When thedropwise addition was completed, the system was refluxed for 2-4 h toobtain 1.6 mol/L cyclopentyl Grignard reagent. Into a mixed solution ofTHF and o-chlorobenzonitrile (50.0 g), 840 mg CuBr was added, andcyclopentyl Grignard reagent (1.6 mol/L, 280 mL) was added dropwiseunder ice bath condition. After the dropwise addition, the system wasrefluxed for 1 h, and then cooled to room temperature, in which 100 mlof water, and then 200 ml of 15% dilute sulfuric acid were added. Thesystem was stirred overnight. THF was rotary dried. The resultant wasextracted with ethyl acetate (EA), dried and purified by passing througha silica gel column to obtain 60 g of Compound A, 2-chlorophenylcyclopentyl ketone, with a yield of 80%.

Step 2: According to the reported method (Bioorganic & MedicinalChemistry 2013, 12, 5098), 20 g (96 mmol) of Compound A was dissolved in400 ml of EA. After Compound A was dissolved, copper bromide (54 g, 242mmol) was added therein, the system was heated to refluxe for 3 h, andthen cooled to room temperature. The solid insolubles were filtered withdiatomite. The filter residue was washed with dichloromethane (DCM). Thewashed solution was combined with the filtrate and then concentrated toobtain yellow oily compound B, 2- chlorophenyl (1- bromocyclopentyl)ketone. After passing through a silica gel column, 22 g of pure compoundB was obtained with a yield of 80%.

Step 3: Ammonia gas was bubbled into 200 ml of ammonia water untilsaturation. Compound B (10 g) was added therein, and the solution wasstirred for 24 h. Compound C was precipitated out, filtered and dried toobtain a brown solid of Compound C (7 g) with a yield of 70%, which wasused directly in the next step.

Step 4: Compound C (5 g) was dissolved in dry THF, HCl gas wasintroduced therein until the pH value of the solution reached 1, andthen the solution was rotary dried to obtain solid hydrochloride. To asingle-neck flask, added was the solid hydrochloride salt. The systemwas placed in an oil bath at 190° C. under nitrogen protection for about20 min, and then cooled to room temperature, neutralized with saturatedsodium bicarbonate solution, extracted with DCM, concentrated andcrystallized to obtain 2.9 g of compound D, a racemate of norketamineHNK, with a yield of 75%. ¹H NMR (400 MHz, CDCl₃): δ7.67 (dd, J = 7.8,1.5 Hz, 1H), 7.37-7.32 (m, 2H), 7.25 (m, 1H), 2.78-2.71 (m, 1H), 2.61(m, 1H), 2.51-2.43 (m, 1H), 2.08-2.0 (m, 1H), 1.88-1.63 (m, 4H).

Step 5: Compound D (1.11 g, 5 mmol) was dissolved in 2 ml methanol,L-tartaric acid (2.5 mmol) was added therein, and the solution wasstirred for 1 h. The solution was dripped into 10 mL of acetone, andstood for crystallization. Then, the system was filtered to obtainL-tartrate crystals. The obtained L-tartrate crystals wererecrystallized for 3 times. The obtained crystals were added into sodiumbicarbonate solution to be neutralized, and then extracted with EA toobtain 165 mg of optically pure compound, E(R)-norketamine. The opticalpurity detected by chiral HPLC was 98.3%ee%, and the yield was 15%.

The chiral HPLC detection was performed with the following steps. In 1ml of ethanol, 1 mg of compound E and 1 mg of control racemic compound Dwere dissolved, respectively, and were analyzed with Agilent 1260-A highperformance liquid chromatography for normal phase uniformity.Chromatography column: Chiralcel-AD-H (4.6 mm × 250 mm), mobile phase A:(n-hexane +0.1% diethylamine), mobile phase B: (ethanol +0.1%diethylamine), A: B=40: 60, and flow rate: 1 mL/min. For Compound E, theretention time of the isomer of R configuration is 6.8 min, and thecorresponding retention time of the isomer of S configuration is 5.3min.

Step 6: Compound E (2.23 g, 10 mmol) was added to 60 ml of THF, andtriethylamine (2.7 mL, 20 mmol) and Boc₂O (3.3 g, 15 mmol) were added.The system was refluxed for 6 h, then cooled, and rotary dried. Theresultant was passed through a silica gel column to obtain 2.92 g ofCompound F with a yeild of 90%. ¹H NMR (400 MHz, CDCl₃): δ7.81 (d,J =8.1 Hz, 1H), 7.40-7.28 (m, 2H), 7.24-7.12 (m, 1H), 6.57 (s, 1H), 3.82(d,J=14.4 Hz, 1H), 2.45-2.36 (m, 1H), 2.28 (m, 1H), 2.04 (m, 1H),1.89-1.56 (m, 4H), 1.27 (s, 9H). ¹³C NMR (100 MHz,CDCl₃): δ207.9, 152.3,134.5, 132.6, 130.3, 130.0, 128.3, 125.2, 78.0, 66.1, 38.5, 37.4, 29.7,27.2, 20.9.

Step 7: Compound F (2.91 g, 9 mmol) was added to 60 mL of dry THF. Thesolution was cooled to -78° C. under argon protection, and 5 mL of HMPAwas added, and then 2 M of LDA in THF solution (12 mL, 24 mmol) wasslowly added dropwise. The system was stirred for 30-40 min, then slowlyheated to -30° C. and stirred for 1 h. Then the system was cooled to-78° C. again and trimethylchlorosilane (TMSCl, 2.6 g, 24 mmol) wasadded. The system was slowly heated to -50° C., stirred for 3 h,saturated ammonium chloride solution was poured in and then thetemperature of the system was elevated to room temperature. The systemwas concentrated by removing the solvent THF, and EA was added forextraction. The organic phase was dried over anhydrous Na₂SO₄. Thesolvent was rotary dried and the resultant was vacuum-dried to obtain anoily substance. The obtained oily substance was dissolved by adding 100mL of anhydrous DCM. The solution was cooled to -15° C., and mCPBA (2.5g, 11 mmol) was added under protection of argon gas. The obtainedsolution was stirred for 1 h, and then 50 mL of DCM was added andfurther stirred for 1 h. Then saturated solution of sodium thiosulfateand sodium bicarbonate (1:1) was poured in, and the system was extractedwith DCM. The solvent was rotary dried and the resultant was vacuumdried to obtain an oily substance. The obtained oily substance wasdissolved in 100 mL THF, and then cooled to -5° C., and tetrabutylammonium fluoride (3 g, 11.4 mmol) was added in the solution. The systemwas stirred for 30 min, and saturated solution of NaHCO₃ was addedtherein. The system was extracted with EA, the solvent was rotary driedand the resultant was vacuum-dried. The obtained substance was thenpassed through a silica gel column to obtain 1.92 g of compound G with ayield of 65%. ¹H NMR (400 MHz, CDCl₃):δ7.81 (d,J = 7.8 Hz, 1H), 7.34 (m,2H), 7.24 (m, 1H), 6.60 (s, 1H), 4.12 (dd,J = 11.7, 6.8 Hz, 1H), 3.87(d,J = 14.4 Hz, 1H), 3.38 (m, 1H), 2.36 (m, 1H), 1.74 (m, 2H), 1.68-1.57(m, 1H), 1.55-1.40 (m, 1H), 1.30 (s, 9H). ¹³C NMR (100 MHz, CDCl₃):209.8, 153.2, 134.1, 133.6, 131.3, 130.8, 129.5, 126.2, 79.3, 72.2,66.5, 40.3, 38.7, 28.1, 19.4.

Step 8: Compound G (680 mg) was dissolved in 5 ml of dry THF. GaseousHCl was introduced into the solution at room temperature untilsaturated. The system was stirred for 4 h, 20 mL dry ether was added,and crystals were precipitated followed by filtration, and 520 mghydrochloride salt of compound H, (2R,6R)-6-hydroxydemethylketamine(HNK) was obtained with a yield of 95%. ¹H NMR (400 MHz, CD₃OD): δ 7.85(m, 1H), 7.65-7.51 (m, 3H), 4.28 (m, 1H), 3.19 (m, 1H), 2.30 (m, 1H),1.81-1.72 (m, 2H), 1.64-1.51 (m, 2H).

Example 2: Synthesis of Compound I5

Compound G (170 mg, 0.5 mmol) was dissolved in 3 mL of dry THF, followedby addition of dry triethylamine (0.28 mL, 2 mmol). Then benzoylchloride (117 µL, 1 mmol) was added under ice bath condition, then thetemperature of the system was slowly raised to room temperature over 1hour, and the system was stirred overnight. Sodium bicarbonate solutionwas added in the system, and the system was extracted with EA. Thesolvent was rotary dried and the resultant was dried in vacuum. Theobtained substance was passed through a silica gel column to obtain 184mg of Compound H₄, N-Boc-(2R,6R)-6- benzoyloxydemethylketamine, with ayield of 85%. ¹H NMR (400 MHz, CDCl₃): δ 8.22-8.19 (m, 2H), 7.91 (m,1H), 7.69-7.64 (m, 1H), 7.56-7.45 (m, 4H), 6.75 (br, 1H), 5.54-5.50 (m,1H), 4.00 (m, 1H), 2.54-2.52 (m, 1H), 2.14-1.93 (m, 3H), 1.86 (m, 1H),1.41 (m, 9H). ¹³C NMR (100 MHz, CDCl₃): δ 202.2, 164.9, 153.3, 133.2,131.4, 131.1, 129.9, 129.7, 129.5, 128.3, 128.0, 126.1, 79.2, 73.8,67.2, 36.6, 34.8, 28.2, 19.0.

Compound H₄ (180 mg) was dissolved in 3 mL of dry THF, gaseous HCl wasintroduced into the solution at room temperature until saturated and thesystem was stirred for 4 h. 15-20 mL of dry ether was added, crystalswere precipitated, and the system was vacuum filtered to obtain 124 mgof Compound I₄, (2R,6R)-6-benzoyloxydemethylketamine hydrochloride salt,with a yield of 83%. ¹H NMR (400 MHz, CD₃OD): δ 9.25-9.20 (brs, 3H),8.21-8.19 (m, 2H), 7.90 (m, 1H), 7.66-7.52 (m, 6H), 5.57 (m, 1H), 3.66(m, 1H), 2.58-2.43 (m, 2H), 2.08-1.97 (m, 3H). ¹³C NMR (100 MHz, CD₃OD):δ 200.1, 164.8, 134.6, 133.4, 131.9, 131.0, 129.9, 129.2, 129.1, 128.4,127.9, 73.9, 68.1, 36.6, 34.9, 19.0.

Compound H (339 mg, 1 mmol) was dissolved in 8 mL of dry THF, followedby addition of dry triethylamine (0.56 ml, 4 mmol), and thenp-dimethylaminobenzoyl chloride (275 mg, 1.5 mmol). The mixture wasrefluxed overnight. The solvent was rotary dried, sodium bicarbonatesolution was added into the mixture, and the mixture was extracted withEA. The solvent of the organic phase was rotary dried and the mixturewas dried in vacuum. The mixture passed through a silica gel column toobtain compound H₅ N-Boc-(2R,6R)-6-p-dimethylaminobenzoyloxydemethylketamine 292 mg with a yield of60%. Compound H₅ (292 mg) was dissolved in 6 mL dry THF, gaseous HCl wasintroduced at room temperature until saturated. The mixture was stirredfor 4 h. Dry ether of 15-20 mL was added, crystals were precipitated,which was vacuum filtered to obtain compound I₅ (2R,6R)-6-p-dimethylaminobenzoyloxydemethylketamine dihydrochloride 148 mg,with a yield of 54%. ¹H NMR (400 MHz, CD₃OD): δ 8.00 (br, 2H), 7.79 (m,1H), 7.44-7.15 (m, 5H), 5.45 (m, 1H), 3.59-3.56 (m, 6H), 3.01-2.92 (m,6H), 2.38-2.35 (m, 1H), 2.19-2.16 (m, 1H) 1.96-1.93 (m, 3H).¹³C NMR (100MHz, CD3OD): δ 200.8, 164.5, 150.6, 134.4, 132.4, 132.1, 131.0, 129.4,128.5, 115.8, 74.1, 67.8, 43.7, 37.0, 35.3, 19.2.

Example 3: Synthesis of Compounds C and D

Compounds C and D were prepared and obtained by the followingpreparation method.

Example 4: Activity Tests 1. Forced Swimming Test

One hour before the forced swimming test (FST), the mice weretransferred to the laboratory. The test was conducted under normal lightcondition and monitored by a digital camera. During the test, the micewere individually placed in transparent glass cylinders (28.5 cm inheight, 14 cm in diameter) filled with 20 cm height of water (23±1° C.).On the first day, the mice were trained for 6 minutes and then removedfrom the cylinder. On the second day, the mice were administered saline,HNK, Compound I5, Compound C, and Compound D, and after different timeperiods, their immobility time was tested. During the last 4 minutes ofthe entire 6-minute swimming test, the static time was recorded throughEthoVision XT (Noldus, Netherlands) of Noldus system. The static timewas defined as passive floating, that is there was no other movementexcept the movements necessary to keep the animal’s head above thewater. After every two to three tests, the water in the cylinders wasreplaced. After the swimming test, the mice were removed from the waterand dried under an infrared lamp.

The mice were given 1 mg (A), 10 mg (B) and 30 mg (C) of HNK and CompundI5 by intragastric administration, respectively, and their immobilitytime was measured after 1 hour and 7 days. The percentage of immobilitytime is expressed as mean ± SEM. *p<0.05, **p<0.01, compared to basetest. Mice of each group was N=8. Saline: saline group; I5: Compound I5treatment group; HNK: 2R,6R-hydroxynorketamine treatment group.

2. Addiction Research Materials and Methods

Animals: Male C57BL/6J mice of 8-12 weeks old were randomly divided intogroups, 10 mice in each group, with body weight of 18-22 g, fed at roomtemperature (22±1° C.), under humidity of (50±10)%, illumination timefrom 8:00 to20:00. The mice had free access to food and water, andadapted to the experimental environment for at least 2-3 days before theexperiments. All experiments were conducted from 8:00 to 16:00.

Behavioral Sensitization Experiment

1.1 Small animal spontaneous activity measurement: An animal spontaneousactivity infrared analysis system consists of a spontaneous activitybox, an infrared probe device and a data acquisition system. The size ofthe spontaneous activity box is 40 cm × 40 cm × 65 cm, with soundisolation and light isolation, and mounted with a ventilation device.The activity statuses of the animals were recorded by the infraredprobe, and the numbers of spontaneous activities of the animals werecalculated. In order to test the effect of drugs on spontaneousactivities of mice, the mice were randomly divided into 4 groups with 10mice in each group. The Groups included: vehicle, I5, C, D (5.0, 10.0,30.0 mg/kg), mor (10 mg/kg). The mice were administratedintragastrically once a day in the morning for 7 consecutive days; afterthat, the drugs withdrew for 7 days (without any treatment). On the15^(th) day, mice in each group were given Veh and the drugs (5.0, 10.0,30.0 mg/kg) by intragastric administration to stimulate. Spontaneousactivity of the mice within 1 hour was measured immediately afteradministration at d1, d7 and d15.

1.2 CPP experiment: A three-room CPP system includes black and whiteboxes (25 cm × 25 cm × 30 cm) at left and right sides, separated by amiddle box (10 cm × 25 cm × 30 cm). During the experiment, mice were putinto the middle box and could freely move to the black and white boxes.A door with the size of 5 cm × 5 cm was arranged between the middle boxand each of the black and white boxes. The experiment adopted a biasedprocedure, which had three stages of pre-test, training, and teststages. During the whole experiment, the environmental conditions suchas light, color and smell in the boxes were guaranteed to be consistent.

Pre-test stage: On days 1-3, the spacer plates between the boxes wereremoved, and all mice were put into the middle box after being injectedwith saline subcutaneously, allowing them to move freely in the boxesfor 15 min, once a day for 3 consecutive days. The residence time of themice in the black and white boxes was respectively recorded to determinethe natural preference of the mice. The mice were trained with thenon-natural preference box as the companion medicine box.

Training stage: On days 4-9, the doors were closed, the mice wererandomly divided into groups of Veh, mor, I5, C, D (5.0, 10.0, 30.0mg/kg), and mor (10 mg/kg), 10 mice in each group. In the morning ofeach odd number of days, all mice were given saline by intragastricadministration and immediately put into non-companion medicine box(black box) for 45 min. In the afternoon of each odd number of days,groups of Veh, mor, I5, C and D (5.0, 10.0, 30.0 mg/kg) wereadministered with the drugs by intragastric administration, and thenimmediately put into the companion medicine box (white box) for 45 min.In each even number of days, the training order was reversed. Theinterval between morning and afternoon trainings was more than 6 hours,and the training time was fixed every day, with 10 mice in each groupfor 6 days.

Test stage: on day 10, the spacer plates were removed, and the mice wereput into the middle box allowing to move freely. At the same time, theresidence time of the mice in the white box within 15 min were recorded.

Statistical analysis: Experimental data were expressed as X±SEM.Graphpad software was used for statistical analysis, and t-test was usedfor comparison between two groups. One-way ANOVA analysis was used forcomparison among multiple groups, and then LSD method was used forpairwise comparison.

3. Position Preference Experiment

Position preference was tested by a three-room system. Mice were trainedwith the non-natural preference box as the companion medicine box.During the training stage, the mice were given saline (Veh), morphine(mor, 10 mg/kg), Compounds I5, C and D (5.0, 10.0, 30.0 mg/kg),respectively. After continuous training for 6 days, the test was carriedout, and the residence times of the mice within 15 min in the white boxwere recorded. Compared with Veh group, * p < 0.05 (n=10).

Example 5: Experimental Results 1. Depression-Like Behavior Test Resultsof the Mice

1 mg of HNK or I5 had no antidepressant effect. Both 10 mg of HNK and I5had antidepressant effect, in which I5 has a long-acting effect, wherethe efficacy thereof substantially did not decrease within 7 days, whilethe efficacy of HNK decreased rapidly within 7 days, and substantiallyhad no effect on the 7^(th) day. Both 30 mg HNK and I5 hadantidepressant effect, in which I5 had a long-acting effect, and theefficacy thereof substantially did not decrease within 7 days, while theefficacy of HNK decayed rapidly within 7 days, and substantially had noeffect on the 7^(th) day.

Compounds C and D had no antidepressant effect with the dose of 30 mg.

Compared with the HNK-treated group, the I5-treated group had asignificant antidepressant effect even at the 7^(th) day afteradministration, as manifested by a reduction in the animals’ immobilitytime during forced swimming. The I5 group had less immobility time.There was no significant difference between the 10 mg and 30 mgtreatment groups, although the 30 mg treated group showed a strongerdecreasing trend. Compounds C and D had no antidepressant effect.

2. Addiction Experiment

Different doses (5 mg, 10 mg, 30 mg) of I5 had no behavioralsensitization effect on mice.

Different doses (5 mg, 10 mg, 30 mg) of C and D had behavioralsensitizing effect on mice.

3. Position Preference Experiment

Different doses (5 mg, 10 mg, 30 mg) of I5 had no position preferenceeffect on mice.

Different doses (5 mg, 10 mg, 30 mg) of C and D induced positionpreference on mice.

The technical features of the above-mentioned embodiments can becombined arbitrarily. For the sake of brevity, all possible combinationsof the technical features in the above-described embodiments are notdescribed. However, as long as there is no contradiction between thecombinations of these technical features, they should be regarded aswithin the scope described in this specification.

The above-mentioned embodiments only represent several embodiments ofthe disclosure, and the descriptions thereof are relatively specific anddetailed, but should not be construed as a limitation on the scope ofthe patent application. It should be noted that a number ofmodifications and improvements may be made by those skilled in the art,without departing from the concept of the disclosure, which all belongto the protection scope of the application. Therefore, the protectionscope of the patent application shall be subject to the appended claims.

11. A compound represented by Formula I, or a salt, stereoisomer ortautomer thereof:

wherein, m is an integer from 0 to 3, and n is an integer from 0 to 4;R₁ and R₂ are each independently one or more selected from a groupconsisting of H, halogen, hydroxyl, amino, cyano, substituted orunsubstituted C₁-C₆ alkyl group, substituted or unsubstituted C₂-C₆alkenyl group, substituted or unsubstituted C₂-C₆ alkynyl group,substituted or unsubstituted C₃-C₁₀ cycloalkyl group, substituted orunsubstituted C₂-C₁₀ heterocyclic group, substituted or unsubstitutedC₁-C₆ alkoxy group, substituted or unsubstituted mono- and di- C₁-C₆alkylamino group, substituted or unsubstituted aryl group, andsubstituted or unsubstituted heteroaryl group; R₃ is halogen; R₄ isselected from a group consisting of H, substituted or unsubstitutedC₁-C₆ alkyl group, substituted or unsubstituted C₁-C₈ acyl group,substituted or unsubstituted arylacyl group, and substituted orunsubstituted heteroarylacyl group; R₅ is selected from a groupconsisting of substituted or unsubstituted C₃-C₁₀ cycloalkylene group,substituted or unsubstituted C₂-C₁₀ heterocyclylene group, substitutedor unsubstituted arylene group, and substituted or unsubstitutedheteroarylene group; R₆ and R₇ are independently selected from a groupconsisting of H, substituted or unsubstituted C₁-C₆ alkyl group,substituted or unsubstituted C₂-C₆ alkenyl group, substituted orunsubstituted C₂-C₆ alkynyl group, substituted or unsubstituted C₃-C₁₀cycloalkyl group, substituted or unsubstituted C₂-C₁₀ heterocyclicgroup, substituted or unsubstituted aryl group, substituted orunsubstituted heteroaryl group, substituted or unsubstituted C₁-C₈ acylgroup, substituted or unsubstituted arylacyl group, and substituted orunsubstituted heteroaryl acyl, or R₆ and R₇, together with N atom towhich R₆ and R₇ are connected, form a substituted or unsubstituted 3 to10-membered monocyclic or bicyclic structure, wherein a group issubstituted means that the group is substituted by a substituentselected from OH; NH_(2;) C₁-C₁₀ alkyl, alkenyl or alkynyl group; C₁-C₁₀alkylamine group; sulfhydryl group; C₁-C₁₀ alkylsulfhydryl group; C₁-C₂₀alkoxy group; C₁-C₁₀ carbonyl group; C₃-C₁₀ cycloalkyl group; 3 to10-membered heterocyclic group with one or more heteroatoms selectedfrom N, S, O and P; C₆-C₂₀ aryl group; C₂-C₂₀ heteroaryl group;nitrocyano; and halogen.
 12. The compound, stereoisomer or tautomerthereof according to claim 11, wherein the compound is represented byFormula II:

.
 13. The compound, stereoisomer or tautomer thereof according to claim11, wherein the compound is represented by Formula III:

.
 14. The compound, or a salt, stereoisomer or tautomer thereofaccording to claim 11, wherein the compound is represented by FormulaIV:

.
 15. The compound, or a salt, stereoisomer or tautomer thereofaccording to claim 11, wherein the compound is shown below:

.
 16. The compound, or a salt, stereoisomer or tautomer thereofaccording to claim 11, wherein the compound is shown below:

.
 17. A compound, or a salt, stereoisomer or tautomer thereof, whereinthe compound is shown below:

wherein R ₈ is H or a protecting group.
 18. The compound, or a salt,stereoisomer or tautomer thereof according to claim 17, wherein thecompound is shown below:

.
 19. The compound, or a salt, stereoisomer or tautomer thereofaccording to claim 17, wherein the compound is shown below:

.
 20. A pharmaceutical composition, comprising the compound, or a salt,stereoisomer or tautomer thereof according to claim 11, and optionally apharmaceutically acceptable carrier.
 21. A pharmaceutical composition,comprising the compound, or a salt, stereoisomer or tautomer thereofaccording to claim 17, and optionally a pharmaceutically acceptablecarrier.
 22. A preparation method of a compound, wherein:

.
 23. A method for anesthesia, alleviating pain, improving cognitivefunction, lung protection, anti-depression, mitigating anxiety andpost-traumatic stress syndrome, or preventing or treating amyotrophiclateral sclerosis or complex regional pain syndrome of a subject,comprising administrating therapeutic effective amount of the compound,or a salt, stereoisomer or tautomer thereof according to claim 11 to thesubject.
 24. The method of claim 23, wherein the pain comprises chronicpain or neuropathic pain; the depression comprises bipolar depression ormajor depressive disorder; and improving of cognitive function comprisespreventing or treating Alzheimer’s dementia or Parkinson’s disease. 25.A method for anesthesia, alleviating pain, improving cognitive function,lung protection, anti-depression, mitigating anxiety and post-traumaticstress syndrome, or preventing or treating amyotrophic lateral sclerosisor complex regional pain syndrome of a subject, comprisingadministrating therapeutic effective amount of the compound, or a salt,stereoisomer or tautomer thereof according to claim 17 to the subject.26. The method of claim 25, wherein the pain comprises chronic pain orneuropathic pain; the depression comprises bipolar depression or majordepressive disorder; and improving of cognitive function comprisespreventing or treating Alzheimer’s dementia or Parkinson’s disease.